Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study

Abstract

Conflict of interestThe authors declare no potential conflicts of interest with respect to this manuscript. AbstractWe investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it to gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01-or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTLs). Of 91 patients enrolled, 85were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival (PFS) (hazard ratio [HR], 0.66; P = 0.084) and improved overall survival rate at 1 year (1-year OS%) (GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363).These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well-tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared to the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86) (P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses.

Future Challenges in Cancer Resistance to Immunotherapy

“…The shift in focus from the direct targeting of the cancer cell towards the stimulation of the anti-tumor response has resulted in encouraging clinical results in humans, but also comes with new problems. Despite promising overall response rates (ORR) for treatment with CPIs, tumor vaccines and ACT or a combination of these, response rates to immunotherapy vary greatly between tumor subtypes, depending partly on their immunogenicities [30,[35][36][37][38][39][40][41][42][43][44]. Primary therapy resistance, defined as a lack of clinical benefit from immunotherapy on tumor growth, exists in a large proportion of patients.…”

Recent advances in chemotherapy for pancreatic cancer: evidence from Japan and recommendations in guidelines

“…In Japan, clinical studies of immunotherapy using peptide vaccines are actively being conducted [67][68][69]. Among them, a randomized phase II study for the Wilms' tumor gene 1 (WT1) vaccine showed promising results [69]; WT1, which is ranked as the top antigen among 75 tumorassociated antigens (TAAs) [70], is one of the most promising TAAs. In this study, gemcitabine plus WT1 vaccine tended to prolong the progression-free survival (HR 0.66; p = 0.084) and improve the OS (HR 0.82; p = 0.363) in comparison with gemcitabine monotherapy.…”

Development of tumour peptide vaccines: From universalization to personalization

“…CTA, which is expressed in various types of human tumours but generally not in normal tissue except in testis, meets some of these criteria; hence, many studies of tumour antigen discovery involve typical CTAs, for example MAGE‐1, NY‐ESO‐1, BAGE, MUC‐1 and SSX‐2 . Since the development of the first‐generation broad‐spectrum WT1 tumour peptide vaccine, whose antigenicity was limited, tumour tissues from patients have been sequenced and tumour mutations analysed to identify a more effective and specific vaccine . Most mutations are not shared between patients, giving rise to patient‐specific antigens.…”